Puberty and its disorders

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Puberty and its disorders
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Puberty

• A stage of human development when sexual
  maturation
• and growth are completed and result in ability to
  reproduce.
• Accelerated somatic growth
• Maturation of primary sexual characteristics
  (gonads and genitals)
• Appearance of secondary sexual characteristics
  (pubic and axillary hair, female breast
  development, male voice changes,...)
• Menstruation and spermatogenesis begin

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Puberty hormonal changes

• Hormonal changes procede physical changes
• Increased stimulation of hypothalamo-pituitary-gon
  adal axis
• gradual activation of the GnRH (LHRH)
• increases frequency and amplitude of LH pulses.
• gonadotropins stimulate secretion of sexual
  steroids (estrogenes and androgenes)
• extragonadal hormonal changes (elevation of
  IGF-I, and adrenal steroids)

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• Extrahypothalamic region - neurotransmiters,
  stress, nutrition
• serotonin, dopamin, GABA norepinefrin,
  neuropeptid Y, glutamic acid
• Ventromedial region
• of hypothalamus
  LH-RH (gonadoliberin)
• Adenohypophysis LH FSH
• 
  Gonads Inhibin
• Estrogens
  Estrogens
• Androgens
  Androgens

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Staging of pubertal development(Tanner)

• Pubertal development is classified according to
  the Tanner standard 5 different stages
• Girls breast (B1-5), pubic hair (Pu1-5),
  axillary hair (A1-5), menarche
• Boys testicular volume gt 4 ml (Te), penis
  enlargement (G1-5), pubic hair (Pu1-5), axillary
  hair (A1-5), spermarche
• Monitoring of the pubertal growth acceleration
• growth velocity is 2-3 times greater than
  prepubertal
• sexual dimorfism in pubertal growth

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Staging of pubertal development in boys
(Tanner)
G1-5, Pu 1-5, A 1-5, testicular volum gt 4 ml
first sign of male puberty
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Staging of pubertal development in girls
(Tanner)
B 1-5, Pu 1-5, A 1-5. (B2 first sign of female
puberty)
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Normal pubertal development
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Diagnostic evaluation

• History
• pubertal history of other family members
• prenatal and perinatal (exposure to exogenous sex
  steroids in intrauterine period birth weight,
  lenght, mechanism of delivery, perinatal
  pathology - resuscitation,..)
• concomitant illnesses, postnatal exposure to sex
  steroids
• time of first sign of puberty
• Physical examination
• - auxologic parameters (height, weight, arm
  span, upper/lower segment ratio,...)
• skin, hair, thyreoid, neurologic findings
• staging of pubertal signs, inspection of external
  genitalia

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Growth charts
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Diagnostic evaluation

• Laboratory
• gonadotropins (FSH, LH) basal and peak after LHRH
  stimulation (prepubertal LH/FSHlt1)
• estradiol
• testosteron (basal value and value after LH
  stimulation)
• adrenal androgens (17-OHP, A-dion,...) and ACTH
• Skeletal maturity (bone age)
• Pelvic sonography (ovarian and uterine size)
• CT or MRI of adrenals, CNS
• Vaginoscopy and vaginal cytology
• Genetic karyotype, DNA analysis

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Bone age (Assessment of biologic maturation)

• X-ray film of the left hand and wrist
• Radius Ulna Small bones (RUS)
• (X-ray of knee important examination for final
  height prediction)
• Different methods of bone age evaluation
  radiographic atlas of skeletal development
• Greulich Pyle
• Tanner-Whitehouse II
• Tanner-Whitehouse III
• Sempé

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Bone age
2 yrs 6 m.
10 yrs
12 yrs
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Pubertal disorders

• Precoccious puberty
• B. Delayed puberty
• C. Child with ambiguous genitalia (intersex)

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Precocious puberty
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Precocious puberty

• Traditional limits for PP are
• the age of 8 years in girls
• the age of 9 years in boys

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Classification

• Central (true), gonadotropin-dependent
• Early stimulation of hypothalamic-pituitary-gonad
  al
• axis.
• Periferal, GnRH independent (precocious
  pseudopuberty)
• The source of sex steroid may be endogenous or
  exogenous,
• gonadal or extragonadal, independent of
  gonadotropins stimulation.

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General terminology

• Complete PP
• Incomplete PP (isolated pubertal sign)
• Isosexual precocity
• early pubertal development appropriate for sex
• Contrasexual (heterosexual) precocity
• inappropriate for sex or appropriate for opposite
  sex

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True precocious puberty(central, GnRH dependent)

• Idiopatic, sporadic or familial (most common)
• CNS abnormalities
• Congenital (hydrocephalus, arachnoid cysts, ...)
• Acquired pathology (posttraumatic, infections,
  radiation,..
• Tumors (LH secreting pituitary microadenoma,
  glioma may be associated with
  neurofibromatosis, hamartoma,..
• Reversible forms - space occuping or
  pressure-associated lesion (abscess,
  hydrocephalus,...)
• Adopted children or children emigrating from
  developping
• countries
• - Improved nutrition, environmental stability
  and psychosocial support

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True precocious puberty(central,
gonadotropin-dependent)

• Always isosexual!
• Bone age is accelerated
• FSH and LH elevation after LH-RH is diagnostic
  test
• (LH/FSH gt 2)
• MRI of CNS is necessary to exclude the neoplasia

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Precocious pseudopuberty in girls(gonadotropin-in
dependent)

• McCune - Albright syndrome
• (polycystic osseous dysplasia, café au lait spots
  and one or more
• endocrinopathies i.e. autonomous ovarian
  activity, pituitary gigantism,..)
• Abnormal function of LH receptor-mutation in
  a-subunit of the G-protein
• Ovarian cysts
• Isolated follicular cysts with E2 production.
  Self-limiting with spontaneous
• regression.
• Ovarian tumors
• Acceleration of bone age
• FSH and LH are low after LH-RH stimulation
• Estrogens are elevated

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Precocious pseudopuberty in boys(gonadotropin-ind
ependent)

• Congenital adrenal hyperplasia (CAH)
• Undiagnosed or inadequately treated simple
  virilising form of CAH caused by 21-hydoxylase
  deficiency.
• Neonatal screening?
• Testotoxicosis
• Activating mutation of LH receptor. AD
  inheredited.
• Tumors
• Gonadal (testosterone-secreting Leydig cell
  tumor)
• Adrenal (adenoma, carcinoma)
• Exogenous androgens (anabolic steroids
  iatrogene, doping)
• Acceleration of bone age
• FSH and LH are low after LH-RH stimulation
• Testicular or adrenal steroids are elevated

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Heterosexual pubertal development in girls

• Clinical findings
• Hirsutisms, acne, virilisation of external
  genitalia, amonorhoe or menstrual
• cycle disturbance
• Elevation of androgens
• - Adrenal (congenital adrenal hyperplasia,
  tumors)
• - Ovarian (polycystic ovary syndrome, tumors)
• - Exogenous (anabolic steroids doping?)
• Bone age is accelerated
• Elevation of testosteron or adrenal androgens

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Heterosexual pubertal development in boys

• Clinical findings
• Gynecomastia, hypogenitalism, eunuchoid body
  proportions
• Elevation of estrogens
• Adrenal or testiscular tumors
• Administration of
• Exogenous estrogens
• Drugs amfetamin, canabis, tricyclic
  antidepresives
• Primary hypogonadism or syndromes with androgen
  insensitivity
• or testosteron synthesis disorders (related to
  ambigous genitalia)

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Variants of normal development

• Premature thelarché (isolated breast enlargement)
• exclude the start of precocious puberty!
• Premature adrenarché (pubic and axillary hairs)
• exclude simple virilising form of CAH!
• Premature menarché
• exclude vaginal bleeding due to trauma of vagine
  or rare ovarian cyst!
• Bone age is not accelerated!
• FSH and LH levels after LH-RH are normal
• Gonadal and adrenal steroid levels are normal
• Pelvic and adrenal ultrasonography is normal

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Gynecomastia

• Breast enlargement in boys
• Physiologic
• (Testosteron is converting to estrogenes in
  liver. Increased sensitivity of E receptors in
  breast to slighly elevated E level)
• in 40 50 boys at the start of puberty
• unilateral or bilateral
• Pathologic
• Unilateral breast tumor (very rare)
• Billateral
• elevated prolactin (PRL) prolactinoma or
  subclinical hypothyreosis with elevation of TSH
• elevated estrogen/testosteron (47,XXY)

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Precoccious puberty-treatment

• Gonadotropin-dependent PP
• Idiopathic
• GnRH (LH-RH) analog (triptorelin) to block LH-RH
  receptor in gonadotroph of pituitary gland
• Organic tumor or cysts
• Surgery
• Gonadotropin independent (pseudopuberty)
• testicular, ovarian or adrenal tumors surgery
• CAH substitution of corticosteroids
• autonomous steroid secretion-estrogens receptor
  antagonists (tamoxifen), steroid synthesis
  inhibitors (ketoconasole), aromatase inhibitors
  (testolacton)

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Delayed puberty
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Delayed puberty - definition

• Initial physical changes of puberty are not
  present
• by age 13 years in girls
• (or primary amenorhoe at 15.5-16y)
• by age 14 years in boys
• Pubertal development is inappropriate
• the interval between first signs of puberty
  and menarche in girls/completition genital growth
  in boys is gt 5 years

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GnRH or gonadotropin dependent I.

• Idiopathic
• sporadic or familial (associated with
  constitutional growth delay)
• Chronic diseases
• with bone age delay and growth retardation due
  to different
• pathophysical mechanismes (malnutrition, anemia,
  acidosis,
• hypoxia,...anorexia nervosa, cystic fibrosis,
  chronic renal insuficiency,..)
• Psychosocial deprivation

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GnRH or gonadotropin dependentII.

• Hypogonadotropic hypogonadism
• Gonadotropin deficiency
• LH only (fertile eunuch syndrome)
• FSH and LH
• - Congenital (genetic, syndromes) - Kallman
  syndrome mutation of KAL gene,
• mutation of DAX1
  gene, Prader-Willi syndrome ,...
• - Acquired - cranial irradiation,
  hemosiderosis, granulomtous disease
• Associated with others pituitary hormones
  deficiencies
• - Congenital empty sella syndrome,
  genetic-transcription factors, disruption
• of pituitary stalk
  (breech delivery),...
• - Acquired tumors, inflamation, irradiation,
  trauma....

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Gonadotropin independent(hypergonadotrophic)

• Boys
• Congenital
• Anorchia
• Chromosomal abnormalities (Klinefelter syndrome,
  Noonan syndrome)
• Acquired
• Autoimunne inflamation (APS)
• Radio or chemotherapy
• Traumatic
• Surgery

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Gonadotropin independent(hypergonadotrophic
hypogonadism)

• Girls
• Congenital
• Billateral ovarian torsion
• Chromosomal abnormalities (Turner syndrome, pure
  gonadal dysgenesis, Noonan syndrome)
• Acquired
• Autoimunne inflamation (APS)
• Radio or chemotherapy
• Traumatic
• Surgery

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Turner syndrome
Turner syndrome

• Karyotype 45,X (45,X/46,XX, structural
  abnormalities of X chromosome)
• Short stature (final height 144-146 cm)
• Gonadal dysgenesis
• Skletal abnormalities
• Cardiac and kidney malformation
• Dysmorfic face
• No mental defect
• Impairment of cognitive function)
• Therapy growth hormone, sex hormone substitution

H. Tuner, 1938
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Congenital adrenal hyperplasia

• Autosomal recessive disorder (1 500 4000)
• The block (complete or partial) in the adrenal
  production of corticosteroids
• (and mineralocorticoids) mostly due to deficiency
  of 21 hydroxylase
• Adrenal androgenes (17-OHP, A-dion)
• elevated but they cannot block ACTH
• Adrenal glands are often enlarged
• Clinical symptomatology
• Salt wasting form (life threatenig disease) (SW)
• hyperkalemia, hyponatremia (dehydratation, shock)
• Girls virilisation of genitalia, heterosexual
  precoccious puberty
• Boys precoccious puberty
• Simple virilising form (without metabolic
  disorder)(SV)
• Simple virilising form partial enzymatic block
  late onset (LO SV)